Download OpioidAnalgesics_2

Morphine
HO- Group is needed for activity
2
HO
3
1
11
4
O
10
15
12
9
13
5
14
H
H
HO
16
8
6
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
3D Structure of Morphine
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
N
CH3
7
• The ‘T-shape’ of this molecule is difficult
to visualize from the 2D representation
• http://www.3dchem.com/molecules.asp?
ID=186#
Brand Names
• AstramorphTM PF; DuramorphTM;
InfumorphTM; KadianTM; MS ContinTM;
MSIRTM; Oramorph SRTM; RMSTM;
RoxanolTM; Roxanol RescudoseTM;
RoxanolTM
• EpimorphTM (Canada); Morphine-HPTM
(Canada); MST-ContinusTM (Mexico);
MS-IRTM (Canada); StatexTM (Canada)
• Morphine is a highly potent opiate analgesic drug
and is the principal active agent in opium and the
prototypical opiate.
• Like other opioids, e.g. Diamorphine (heroin),
morphine acts directly on the central nervous
system (CNS) to relieve pain, and at synapses of
the nucleus accumbens in particular.
• Morphine is highly addictive when compared to
other substances, and tolerance and physical and
psychological dependences develop very rapidly.
Administration of Morphine
• Parenterally as subcutaneous, intravenous,
or epidural injections.
• When injected, particularly intravenously,
morphine produces an intense contraction
sensation in the muscles due to histamine
release and also produces a very intense
'rush' which is mediated by several different
receptors in the CNS.
• The military sometimes issues morphine
loaded in an autoinjector.
Administration
• Orally, it comes as an elixir, concentrated
solution, powder (for compounding) or in tablet
form.
• Morphine is rarely supplied in suppository form.
Due to its poor oral bioavailability, oral morphine
is only one-sixth to one-third of the potency of
parenteral morphine.
• Morphine is available in extended release
capsules for chronic administration, as well as
immediate-release formulations.
Side Effects
• Morphine has many side effects. The most
dangerous is respiratory depression. With higher
doses or in frail patients, the respiratory rate
decreases, the patient becomes increasingly
sedated, and the pupils very small.
• Common side effects are nausea and vomiting
due to a central action of morphine stimulating
one of the centres in the brain concerned with
vomiting called the chemotactic trigger zone.
Side Effects
• Other central nervous system side effects of
morphine are cough suppression, sedation,
and dependence leading to addiction.
• Morphine also has an effect on the muscle of
the bowel and urinary tract, causing the
sphincter to contract and reduce the
peristalsis (the wavelike movements of the
bowel muscle that propel its contents
forwards). This results in a delayed emptying
of the stomach, constipation, and may also
lead to urinary retention.
Side Effects
• Morphine can also cause histamine
release, which causes itching of the skin
and nose and a mild flushing of the skin.
How do opioid analgesics work?
There are three known types of receptors
for opioid analgesics: , , and .
• http://www.thirteen.org/closetohome/ani
mation/opi-anim2-main.html
• http://thebrain.mcgill.ca/flash/i/i_03/i_03
_m/i_03_m_par/i_03_m_par_heroine.ht
ml#drogues
• http://thebrain.mcgill.ca/flash/d/d_03/d_
03_cr/d_03_cr_que/d_03_cr_que.html
Overview: Opioid Receptors
• Opioid receptors are a group of Gprotein coupled receptors with opioids
as ligands.
• The endogenous opioids are
dynorphins, enkephalins and
endorphins.
The mu Receptor
• The main endogenous ligands for the
mu receptor are the endorphins,
peptides having 31 amino acids, with
Tyr at the N-terminal end (note that the
phenolic -OH group of tyrosine
resembles that of morphine)
Tyrosine and Morphine
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
7
N
CH3
The  receptor seems to be the major
opioid target
• Activation of the μ receptor by an agonist such as
morphine causes analgesia, sedation, reduced
blood pressure, itching, nausea, euphoria,
decreased respiration, miosis (constricted pupils)
and decreased bowel motility often leading to
constipation.
• Some of these effects, such as sedation, euphoria
and decreased respiration, tend to disappear with
continued use as tolerance develops. Analgesia,
miosis and reduced bowel motility tend to persist;
little tolerance develops to these effects.
The  receptor
• Tolerance develops to different effects at
different rates largely because these effects
are caused by activation of different μreceptor subtypes.
• Stimulation of μ1-receptors blocks pain while
stimulation of μ2-receptor causes respiratory
depression and constipation.
Overview: Opioid Receptors
• Activation of the δ-Opioid receptor produces some
analgesia, although not as much as activation of the mu
receptor
• The natural ligands for this receptor are the enkephalins,
pentapeptides with the structures: Tyr-Gly-Gly-Phe-Met or
Tyr-Gly-Gly-Phe-Leu
• There is a recent interest in using delta agonists as
antidepressants.
Overview: Opioid Receptors
• κ-Opioid receptors are also involved with
analgesia, but activation also produces
marked nausea and dysphoria (sadness,
irritability, anxiety)
• The main endogenous ligands of the k
receptor are the dynorphins, another class
of endogenous peptide
Heroin
HO- Group is needed for activity
2
AcO
2
HO
Easily enzymatically hydrolyzed to AcOH and HO-Ar
3
3
1
1
11
4
11
4
12
O
10
15
O
16
13
14
H
H
8
6
13
5
N
CH3
10
15
14
H
H
AcO
16
9
9
5
HO
12
8
6
N
CH3
7
7
Morphine (Astramorph)
HO- Group not important to activity
Heroin (Diamorphine)
(2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
Codeine
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO
3
CH3O
1
11
4
12
O
10
15
O
9
13
5
14
H
H
HO
16
8
6
N
H
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
N
CH3
HO
Codeine (5X LESS potent than morphine)
Uses of Codeine
• Approved indications for codeine include:
• ･Cough, though its efficacy in low dose over the
counter formulations has been disputed.
• Diarrhea
• Moderate to severe pain･Irritable bowel syndrome
• Codeine is sometimes marketed in combination
preparations with paracetamol (acetaminophen) as
co-codamol (best known in North America as
Tylenol 3), with aspirin as co-codaprin or with
ibuprofen. These combinations provide greater
pain relief than either agent (drug synergy; see
synergy).
Commercial Products Containing Codeine
Codeine
• Codeine is considered a prodrug, since it is
metabolised in vivo to the principal active
analgesic agent morphine. It is, however, less
potent than morphine since only about 10% of the
codeine is converted. It also has a
correspondingly lower dependence-liability than
morphine.
• The conversion of codeine to morphine occurs in
the liver and is catalysed by the cytochrome P450
enzyme CYP2D6. Approximately 6ﾐ10% of the
Caucasian population have poorly functional
CYP2D6 and codeine is virtually ineffective for
analgesia in these patients.
Hydrogenation of morphine’s C=C
produced dihydromorphine
2
HO
3
11
4
12
O
5
14
H
H
HO
8
6
3
1
11
4
10
15
16
H2 / Pd
9
13
2
HO
1
12
O
10
15
9
N
13
5
14
H
CH3
7
Morphine (Astramorph)
16
N
H
HO
8
6
CH3
7
Dihydromorphine
Dihydromorphine is slightly stronger than morphine as
an analgesic with a nearly identical side-effect profile,
and is a somewhat more active euphoriant
However, this led to a cmpd with
improved activity
2
HO
3
11
4
12
O
5
14
H
[O]
N
8
6
1
11
16
H
HO
3
4
10
15
9
13
2
HO
1
7
Dihydromorphine
12
O
10
15
9
13
5
14
H
CH3
H
O
16
8
6
N
CH3
7
Hydromorphone
(7X more potent than morphine)
Hydromorphone is a drug developed in Germany in the
1920s and introduced to the mass market beginning in 1926.
It is used to relieve moderate to severe pain and severe,
painful dry coughing.
2
HO
3
1
11
4
O
10
15
12
9
13
5
14
H
H
O
16
8
6
N
CH3
7
Oxidized -OH
Reduced C=C
Hydromorphone
(Dilaudid)
(7X more potent than morphine)
• Hydromorphone is known by the trade name,
"Dilaudid”.
• Another extended-release version called
Hydromorph Contin, manufactured as controlled
release capsules, continues to be produced.
Hydromorphone
• Compared to morphine and heroin,
hydromorphone has superior solubility and
speed of onset and less troublesome side effect
and dependence liability profile.
• Many chronic pain patients find that
hydromorphone has a spectrum of actions which
suit them just as well as morphine, and better
than synthetics like methadone or levorphanol in
alleviating suffering, as contrasted with simple
pain of equal objective intensity.
Similar synthetic manipulations make
hydrocodone more potent than codeine
2
MeO
Methylated OH,
thus belongs to codein class
3
1
11
4
12
O
10
15
16
9
13
5
14
H
N
CH3
H
O
8
6
7
Oxidized -OH
Reduced C=C
Hydrocodone
(Vicodin, Lortab, Dicodin)
(7X more potent than morphine)
• Hydrocodone (marketed as Vicodin, Lortab, Dicodin, others)
• Usually sold mixed with other milder analgesics, such as
acetaminophen (Tylenol, paracetamol)
• Such combination products are more effective analgesics and also limit
the potential for abuse.
Oxycodone
HO- Group is needed for activity
CH3 group reduces potency
CH3O
2
HO
3
1
10
15
12
O
16
oxidized OH
H
OH
9
13
5
14
H
H
HO
O
11
4
8
6
N
N
CH3
O
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
Reduced C=C
-OH group increases potency
Oxycodone
(Percocet = mix with acetaminophen)
(Percodan = mix with aspirin)
(OxyContin = with binders, continuous release)
(OxyNorm = immediate release, inert fillers)
(equal to morphine in potency)
(orally bioavailable)
Oxycodone: Uses
• Percocet tablets (Oxycodone with
acetaminophen) are routinely prescribed for
post-operative pain control.
• Both immediate release oxycodone (OxyNorm in
the UK) and sustained-release oxycodone
(OxyContin in the UK) are prescribed for pain
due to cancer more than for any other condition.
Oxycodone: Recreational Use
• Unlike Percocet, whose potential for abuse is
limited by the presence of acetaminophen
(paracetamol), OxyContin contains only
oxycodone and inert filler.
• Abusers simply crush the tablets, then either
ingest the resulting powder orally,
intranasally, via intravenous, intramuscular or
subcutaneous injection (by dissolving the
powder), or rectally to achieve rapid
absorption into the bloodstream.
Oxycodone:
Recreational Use
• Injection of OxyContin is particularly dangerous since it
contains binders which enable the time release of the drug.
• Often mistaken as the time release, the outside coating of
the pill is merely used as a color code for different dosage
amounts.
• The vast majority of OxyContin-related deaths are
attributed to ingesting substantial quantities of oxycodone
in combination with another depressant of the central
nervous system such as alcohol or benzodiazepines.
Oxymorphone
HO- Group is needed for activity
HO
2
HO
3
1
11
4
10
15
12
O
O
16
9
13
5
14
H
H
HO
HO- Group is needed for activity
8
6
oxidized OH
N
CH3
7
H
OH
N
CH3
O
Reduced C=C
-OH group increases potency
Morphine (Astramorph)
Oxymorphone
HO- Group not important to activity
(Numorphan = injectable, suppository)
Opana = tablet, OpanaER = extended release
(8X more potent than morphine)
(poorly orally bioavailable,
necessitating the inclusion of large amounts
of drug in Opana tablets)
Thebaine
CH3O
O
H
N
CH3
CH3O
Thebaine (paramorphine) is an opiate alkaloid. A minor constituent of opium, thebaine
is chemically similar to both morphine and codeine, but produces stimulatory, with
strychnine-like convulsions, rather than depressant effects. Thebaine is not used
therapeutically, but is converted industrially into a variety of compounds including
oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and
etorphine.
It is controlled in Schedule II of the Controlled Substances Act as well as under
international law. Thebaine is listed as a Class A drug under the Misuse of Drugs Act
1971 in the United Kingdom.
Changing substitutents on nitrogen can either
improve agonist activity…or create
antagonists!
2
HO
12
10
15
16
11
12
O
14
H
H
8
6
N
13
5
CH3
7
Morphine (Astramorph)
14
H
H
HO
8
6
3
1
11
4
10
15
16
H2
C
9
9
13
2
HO
1
4
11
5
HO
3
1
4
O
2
HO
3
N
12
O
7
More potent than morphine.
14
H
Ph
H
HO
16
9
13
5
C
H2
10
15
8
6
H
C
N
C
H2
CH2
7
Nalorphine
An antagonist at the morphine receptor!!!
Nalorphine , derivative of morphine that acts to reverse the
effects of morphine and other narcotics .
It counteracts narcotic-induced nervous system and respiratory
system depression but is not effective against depression
induced by other sedatives such as barbiturates .
Nalorphine
2
HO
3
11
4
12
O
5
HO
H
8
6
12
O
14
H
1
11
16
9
13
3
4
10
15
N
10
15
5
14
H
Morphine (Astramorph)
H
HO
16
9
13
CH3
7
N-allyl group changes biological activity
from agonist to antagonist.
2
HO
1
8
6
H
C
N
C
H2
CH2
7
Nalorphine
An antagonist at the morphine receptor!!!
• Nalorphine and other narcotic antagonists are useful in
reversing the effects of narcotic overdoses.
• Because nalorphine causes withdrawal symptoms in
addicts, it is administered to apparent ex-addicts to
determine if they have returned to drug use.
•
Nalorphine is marketed under the trade name Nalline.
Still more potent antagonists can be made by
incorporating the same structural changes used to
make morphine a more potent analgesic
2
HO
3
1
3
2
HO
1
3
1
11
4
10
15
12
O
13
14
H
H
8
6
H
C
N
C
H2
7
O
16
9
13
5
12
O
14
H
OH
CH2
O
Nalorphine
10
15
12
11
4
11
4
16
9
5
HO
2
HO
8
6
H
C
N
7
Naloxone
C
H2
O
16
9
13
5
CH2
10
15
14
H
OH
8
6
N
C
H2
7
Naltrexone
2
HO
3
1
11
4
12
O
16
9
13
5
O
10
15
14
H
OH
8
6
H
C
N
C
H2
CH2
7
Naloxone
• Naloxone is a drug used to counter the effects of
opioid overdose, for example heroin or morphine
overdose.
• Naloxone is specifically used to counteract lifethreatening depression of the central nervous
system and respiratory system.
• It is marketed under various trademarks including
Narcan, Nalone, and Narcanti, and has sometimes
been mistakenly called "naltrexate." It is not to be
confused with Naltrexone, another opioid receptor
antagonist with qualitatively different effects.
Naltrexone
2
HO
3
1
3
2
HO
1
3
1
11
4
10
15
12
O
13
14
H
H
8
6
H
C
N
C
H2
7
O
16
9
13
5
12
O
14
H
OH
CH2
O
Nalorphine
10
15
12
11
4
11
4
16
9
5
HO
2
HO
8
6
H
C
N
7
Naloxone
C
H2
O
16
9
13
5
CH2
10
15
14
H
OH
8
6
N
C
H2
7
Naltrexone
Naltrexone
• Naltrexone is an opioid receptor antagonist
used primarily in the management of alcohol
dependence and opioid dependence.
• It is marketed in generic form as its
hydrochloride salt, naltrexone hydrochloride,
and was formerly marketed using the trade
name Revia.
• In some countries, an extended-release
formulation is marketed under the trade name
Vivitrol. It should not be confused with
naloxone, which is used in emergency cases
of overdose rather than for longer term
dependence control.